Diagnostic value of H3F3A mutations in giant cell tumour of bone compared to osteoclast-rich mimics

Driver mutations in the two histone 3.3 (H3.3) genes, H3F3A and H3F3B, were recently identified by whole genome sequencing in 95% of chondroblastoma (CB) and by targeted gene sequencing in 92% of giant cell tumour of bone (GCT). Given the high prevalence of these driver mutations, it may be possible to utilise these alterations as diagnostic adjuncts in clinical practice. Here, we explored the spectrum of H3.3 mutations in a wide range and large number of bone tumours (n 5 412) to determine if these alterations could be used to distinguish GCT from other osteoclast-rich tumours such as aneurysmal bone cyst, nonossifying fibroma, giant cell granuloma, and osteoclast-rich malignant bone tumours and others. In addition, we explored the driver landscape of GCT through whole genome, exome and targeted sequencing (14 gene panel). We found that H3.3 mutations, namely mutations of glycine 34 in H3F3A, occur in 96% of GCT. We did not find additional driver mutations in GCT, including mutations in IDH1, IDH2, USP6, TP53. The genomes of GCT exhibited few somatic mutations, akin to the picture seen in CB. Overall our observations suggest that the presence of H3F3A p.Gly34 mutations does not entirely exclude malignancy in osteoclast-rich tumours. However, H3F3A p.Gly34 mutations appear to be an almost essential feature of GCT that will aid pathological evaluation of bone tumours, especially when confronted with small needle core biopsies. In the absence of H3F3A p.Gly34 mutations, a diagnosis of GCT should be made with caution.

Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone

It is recognized that some mutated cancer genes contribute to the development of many cancer types, whereas others are cancer type specific. For genes that are mutated in multiple cancer classes, mutations are usually similar in the different affected cancer types. Here, however, we report exquisite tumor type specificity for different histone H3.3 driver alterations. In 73 of 77 cases of chondroblastoma (95%), we found p.Lys36Met alterations predominantly encoded in H3F3B, which is one of two genes for histone H3.3. In contrast, in 92% (49/53) of giant cell tumors of bone, we found histone H3.3 alterations exclusively in H3F3A, leading to p.Gly34Trp or, in one case, p.Gly34Leu alterations. The mutations were restricted to the stromal cell population and were not detected in osteoclasts or their precursors. In the context of previously reported H3F3A mutations encoding p.Lys27Met and p.Gly34Arg or p.Gly34Val alterations in childhood brain tumors, a remarkable picture of tumor type specificity for histone H3.3 driver alterations emerges, indicating that histone H3.3 residues, mutations and genes have distinct functions.

Acute Upper Limb Ischemia, a Rare Presentation of Giant Cell Arteritis

Giant cell arteritis (GCA) is a systemic large vessel vasculitis, with extracranial arterial involvement described in 10-15% of cases, usually affecting the aorta and its branches. Patients with GCA are more likely to develop aortic aneurysms, but these are rarely present at the time of the diagnosis. We report the case of an 80-year-old Caucasian woman, who reported proximal muscle pain in the arms with morning stiffness of the shoulders for eight months. In the previous two months, she had developed worsening bilateral arm claudication, severe pain, cold extremities and digital necrosis. She had no palpable radial pulses and no measurable blood pressure. The patient had normochromic anemia, erythrocyte sedimentation rate of 120 mm/h, and a negative infectious and autoimmune workup. Computed tomography angiography revealed concentric wall thickening of the aorta extending to the aortic arch branches, particularly the subclavian and axillary arteries, which were severely stenotic, with areas of bilateral occlusion and an aneurysm of the ascending aorta (47 mm). Despite corticosteroid therapy there was progression to acute critical ischemia. She accordingly underwent surgical revascularization using a bilateral carotid-humeral bypass. After surgery, corticosteroid therapy was maintained and at six-month follow-up she was clinically stable with reduced inflammatory markers. GCA, usually a chronic benign vasculitis, presented exceptionally in this case as acute critical upper limb ischemia, resulting from a massive inflammatory process of the subclavian and axillary arteries, treated with salvage surgical revascularization.

Granulocyte macrophage colony-stimulating factor enhances the modulatory effect of cytokines on monocyte-derived multinucleated giant cell formation and fungicidal activity against Paracoccidioides brasiliensis

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Differentially expressed genes in giant cell tumor of bone

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Peripheral giant cell granuloma. An immunohistochemical and ultrastructural study.

OBJECTIVE: To study the nature of multinucleated and mononuclear cells from peripheral giant cell granuloma (PGCG). MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded sections of 40 cases of PGCG were immunohistochemically stained for vimentin, alpha I-antichymotrypsin, CD68, S-100 protein, lysozyme, leucocyte common antigen (LCA), factor VIII-related antigen and muscle cell actin. Six cases of PGCG were also studied by transmission electron microscopy. RESULTS: Vimentin, alpha I-antichymotrypsin and CD68 were expressed in both the mononuclear and multinucleated giant cells. Dendritic mononuclear cells, positive for S-100 protein, were noted in 67.5% of the lesions, whereas lysozyme and leucocyte common antigen were detected in occasional mononuclear cells. Ultrastructural examination showed mononuclear cells with signs of phagocytosis and sometimes interdigitations with similar cells. Others presented non-specific characteristics and the third type exhibited cytoplasmic processes and occasional Birbeck granules. Some multinucleated giant cells showed oval nuclei, abundant mitochondria and granular endoplasmic reticulum whereas others presented with irregular nuclei and a great number of cytoplasmic vacuoles. CONCLUSIONS: Immunohistochemical and ultrastructural results suggest that PGCGs of the jaws are composed mainly of cells of the mononuclear phagocyte system and that Langerhans cells are present in two thirds of the lesions.

Effect of dietary supplementation with vitamin E and stocking density on macrophage recruitment and giant cell formation in the teleost fish, Piaractus mesopotamicus

The effect of dietary supplementation with 0, 100 and 450 mg of vitamin E (DL-α tocopheryl acetate)/kg of a dry diet on the kinetics of macrophage recruitment and giant cell formation in the pacu, maintained at different stocking densities (5 kg/m3 and 20 kg/m3), was investigated by insertion of round glass coverslips into the subcutaneous connective tissue. After a feeding period of 18 weeks, the coverslips were implanted and later removed for examination at 2, 7 and 15 days post-implantation. Fish fed diets supplemented with 450 mg of vitamin E showed an increase (P<0.05) in the accumulation of macrophages, foreign body giant cells and Langhans type cells. The kinetics of macrophage recruitment and giant cell formation on the glass coverslips appeared to be strongly influenced by vitamin E supplementation, since fish fed a basal diet and held at high stocking densities showed low numbers of adhering cells on the coverslips, and high concentrations of plasma corticosteroids. On the other hand, fish given a diet supplemented with 450 mg of vitamin E did not show a similar difference in plasma cortisol concentrations related to stocking density. The effect of cortisol concentrations on carbohydrate metabolism, analysed by assessment of plasma glycaemia, was not clear. Blood glucose concentrations did not vary substantially with the different treatments examined. These results suggest that vitamin E may contribute to the efficiency of the fish's inflammatory response by increasing macrophage recruitment and giant cell formation in the foreign body granulomatous reaction. Vitamin E appeared to act on the stress response of pacus by preventing a stress-related immunosuppression. © 2005 Elsevier Ltd. All rights reserved.

Differential Expression of ADAM23, CDKN2A (P16), MMP14 and VIM Associated with Giant Cell Tumor of Bone

Though benign, giant cell tumor of bone (GCTB) can become aggressive and can exhibit a high mitotic rate, necrosis and rarely vascular invasion and metastasis. GCTB has unique histologic characteristics, a high rate of multinucleated cells, a variable and unpredictable growth potential and uncertain biological behavior. In this study, we sought to identify genes differentially expressed in GCTB, thus building a molecular profile of this tumor. We performed quantitative real-time polymerase chain reaction (qPCR), immunohistochemistry and analyses of methylation to identify genes that are putatively associated with GCTB. The expression of the ADAM23 and CDKN2A genes was decreased in GCTB samples compared to normal bone tissue, measured by qPCR. Additionally, a high hypermethylation frequency of the promoter regions of ADAM23 and CDKN2A in GCTB was observed. The expression of the MAP2K3, MMP14, TIMP2 and VIM genes was significantly higher in GCTB than in normal bone tissue, a fact that was confirmed by qPCR and immunohistochemistry. The set of genes identified here furthers our understanding of the molecular basis of GCTB.

Central Granular Cell Odontogenic Tumor of the Maxilla

The central granular cell odontogenic tumor (CGCOT) is a rare benign odontogenic neoplasm composed of varying amounts of large eosinophilic granular cells and apparently inactive odontogenic epithelium. It tends to occur as a small asymptomatic swelling in the posterior region of the mandible with nonaggressive appearance. We report an unusual case of CGCOT in the maxillary region with clinical features of malignancy. The patient underwent surgical treatment, and the 2-year follow-up revealed no signs of recurrence. Central granular cell odontogenic tumor is a very rare condition with few cases reported, especially in the maxillary region. This case highlights the possibility of aggressive behavior by these lesions.

Giant cell bone lesions in the craniofacial region: a diagnostic and therapeutic challenge

Background: Giant cell tumors of bone (GCTs) are common in the long bones, but rare in the craniofacial region, with only 1% of cases occurring in the latter. Clinical, radiological, and anatomical diagnosis of this locally aggressive disease, which occurs in response to trauma or neoplastic transformation, poses a major challenge in clinical practice. Methods: The present study describes a series of 4 cases and highlights the main features of the differential diagnosis and treatment of these lesions: GCT, giant cell reparative granuloma (GCRG), and the brown tumor of hyperparathyroidism. Results: GCT presents as a benign neoplasm, most typically affecting the knees, and rarely in the temporal and sphenoid bones. It is radiologically indistinguishable from GCRG due to its lytic, poorly defined appearance. The distinction can only be made microscopically, as the presence of multinucleated giant cells scattered throughout the stroma and the absence of a history of trauma favor a diagnosis of GCT. The brown tumor of hyperparathyroidism occurs with rapid, localized osteoclast activity secondary to the effects of increased parathyroid hormone (PTH) levels; parathyroid examination is indispensable. Conclusion: The diagnosis and treatment of these lesions poses a major challenge due to their similar clinical presentation and radiological appearance. Accurate diagnosis is essential for definition of appropriate management, as complete resection is the goal in GCT and GCRG to avoid recurrence, whereas the brown tumor often yields to treatment of the underlying hyperparathyroidism.

Recurrent giant cell tumor of long bones: analysis of surgical management

Treatment of giant cell tumor of bone (GCT) often is complicated by local recurrence. Intralesional curettage is the standard of care for primary GCTs. However, there is controversy whether intralesional curettage should be preferred over wide resection in recurrent GCTs.

Giant cell tumor of bone: risk factors for recurrence

Many surgeons treat giant cell tumor of bone (GCT) with intralesional curettage. Wide resection is reserved for extensive bone destruction where joint preservation is impossible or when expendable sites (eg, fibular head) are affected. Adjuvants such as polymethylmethacrylate and phenol have been recommended to reduce the risk of local recurrence after intralesional surgery. However, the best treatment of these tumors and risk factors for recurrence remain controversial.